Oncogenic RAS alleles are among the most frequently detected mutations in patients with cancer, and are present in 25-44% of patients with acute myeloid leukemia (AML). We generated two novel models of oncogenic K-ras mediated hematopoietic disease through expression of oncogenic K-ras at physiologic levels from its endogenous promoter in the murine hematopoietic system using Mx1-Cre-mediated recombination. First, we established a model of myeloproliferative disease (MPD) induced by oncogenic K-ras alone. Second, we established a model of acute promyelocytic leukemia (APL) induced by the cooperative effects of oncogenic K-ras and a PML-RARalpha transgene. These mouse models validate the contribution of oncogenic RAS to leukemogenesis and implicate the RAS signaling pathway as an important target for therapeutic inhibition in patients with AML. These oncogenic K-ras models of hematopoietic disease represent valuable preclinical platforms to test the feasibility of RAS-targeted therapy. Further investigations will involve: Specific Aim 1 - Use of ras pathway inhibitors on the oncogenic K-ras induced myeloproliferative disease to ascertain therapeutic efficacy, elucidate the mechanism of action of farnesyltransferase inhibitors, and determine the downstream ras effector pathways critical for disease. Specific Aim 2 - Treatment of the APL disease induced by the cooperative effects of oncogenic K-ras and PML-RARalpha with ras pathway inhibitors and neutrophil elastase inhibitors alone, and in combination with all trans retinoic acid (ATRA) to test promising new synergistic therapies for APL. Specific Aim 3 - Identification of the leukemic stem cell in APL, and the signal transduction pathways involved in promoting cellular self-renewal through detailed characterization of purified populations of hematopoietic stem cells and myeloid progenitors from diseased mice with APL.